Obstetric anesthesia management of the patient with cardiac disease.

Cardiovascular disease is the leading cause of maternal mortality in much of the developed world. Risk stratification models can predict which patients are at greatest risk for maternal or fetal morbidity or mortality. Particular cardiac diseases hold significant risk of mortality during pregnancy including pulmonary hypertension, aortic aneurysm, left-ventricular outflow tract obstruction, and severe cardiomyopathy. High-risk patients should deliver at high-resource hospitals under the care of experts in cardiology, obstetrics, perinatology, neonatology and anesthesiology. The obstetric anesthesiologist should formulate delivery plans for cardiac monitoring, labor analgesia, cesarean anesthesia, postpartum monitoring, as well as plans for obstetric or cardiac emergencies. Carefully co-ordinated multidisciplinary care of pregnant women with cardiac disease can result in successful outcomes.

Sequential incremental doses of bisacodyl increase the diagnostic accuracy of colonic manometry.

BACKGROUND: Colonic manometry is the standard diagnostic modality for evaluating colonic motility in children. Intraluminal bisacodyl is routinely used to trigger high-amplitude propagating contractions (HAPCs), a feature of normal colonic motility. Usually, only a single dose (0.2 mg/kg) is suggested. We retrospectively explored whether the use of an additional higher (0.4 mg/kg) dose of bisacodyl increases the yield of colonic manometry. METHODS: In 103 children (median age: 8.8 years, range 3.2-15.7 years) with a diagnosis of slow transit constipation, colonic motility was recorded for 1 h before and 1 h after each of two incremental doses of bisacodyl (low, L, dose: 0.2 mg/kg, max 10 mg; high, H, dose: 0.4 mg/kg, max 20 mg) and the characteristics of HAPCs analyzed. KEY RESULTS: High-amplitude propagating contractions were seen in 85 children. H dose significantly increased the proportion of patients with fully propagated HAPCs (H dose: 57/103 [55%], L dose: 27/103 [26%], p < 0.001), paralleling the significant decrease in the proportion with partially propagated HAPCs (H dose: 29/103 [28%], L dose: 47/103 [46%], p < 0.01). Mean HAPC number significantly increased throughout the colon at H compared to L dose (7.2 ± 5.05 vs 5.6 ± 5.1, p < 0.05). Finally, the proportion of patients with normal pressure wave morphology of HAPCs significantly increased with higher dose (H dose: 55/85 [65%], L dose: 27/85 [32%], p < 0.001). CONCLUSIONS & INTERFERENCES: An additional higher dose of bisacodyl during colonic manometry improves colonic neuromuscular function suggesting its use might improve interpretation and decision making in children with slow transit constipation.

Efficacy of the neurokinin-1 receptor antagonist aprepitant in children with cyclical vomiting syndrome.

BACKGROUND: Aprepitant (Emend, Merck Sharp & Dohme Ltd, Haarlem, the Netherlands), a neurokinin-1 receptor antagonist, prevents vomiting in a range of conditions. No data are available on its use in children with cyclical vomiting syndrome (CVS). AIM: We investigated the efficacy of aprepitant as prophylactic treatment or acute intervention in CVS children refractory to conventional therapies. METHODS: Forty-one children (median age: 8 years) fulfilling NASPGHAN criteria treated acutely (RegA) or prophylactically (RegP) with aprepitant were retrospectively reviewed. Primary outcome was the clinical response (decrease in frequency and intensity of CVS episodes). Secondary outcomes were: number of CVS episodes/year, number of hospital admissions/year, CVS episode duration, number of vomits/h, symptom-free interval length (days), and school attendance percentage. The follow-up period was 18-60 months. RESULTS: Sixteen children received RegP and 25 RegA. One child on RegP stopped treatment due to severe migraine. At 12-months on intention-to-treat analysis, 13 children on RegP (81%) achieved either complete (3/16, 19%) or partial (10/16, 62%) clinical response. On RegA, 19 children (76%) had either complete (3/25, 12%) or partial (16/25, 64%) response (P = 0.8 vs. RegP). In both RegP and RegA, there was a significant decrease in CVS episodes/year, hospital admission number/year, CVS episode length, number of vomits/h, as well as an increase in symptom-free interval duration and school attendance percentage. Side effects were reported only in RegP (5/16, 31%) including hiccough (3/16, 19%), asthenia/fatigue (2/16, 12.5%), increased appetite (2/16, 12.5%), mild headache (1/16, 6%) and severe migraine (1/16, 6%). CONCLUSION: Aprepitant appears effective for both acute and prophylactic management of paediatric cyclical vomiting syndrome refractory to conventional therapies.

Dilated intercellular space diameter as marker of reflux-related mucosal injury in children with chronic cough and gastro-oesophageal reflux disease.

BACKGROUND: The diagnostic corroboration of the relationship between gastro-oesophageal reflux disease (GERD) and chronic cough remains challenging. AIMS: To compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro-oesophageal reflux (GER)-related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER-related cough. METHODS: Forty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2-3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance-pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups. RESULTS: A significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 µm) and controls (0.5 ± 0.2 µm, P < 0.001), whereas there was no difference between GrC and GERD group (1 ± 0.3 µm, NS). No difference was found in the mean ISD between GrC children with or without pathological oesophageal acid exposure time (1 ± 0.3 vs. 0.9 ± 0.2 µm), and there was no correlation between ISD and any reflux parameter. Finally, there was no correlation between ISD and distal baseline impedance values (r:-0.35; NS). CONCLUSIONS: In children with reflux-related cough, dilated intercellular space diameter appears to be an objective and useful marker of oesophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients where the diagnosis is uncertain. In children with reflux-related cough, baseline impedance levels have no role in identifying reflux-induced oesophageal mucosal ultrastructural changes.

High-resolution colonic manometry accurately predicts colonic neuromuscular pathological phenotype in pediatric slow transit constipation.

BACKGROUND: Severe pediatric slow transit constipation (STC) is commonly due to intrinsic colonic neuromuscular disease. We sought to correlate neuromuscular histological phenotypes in pediatric STC with colonic manometric phenotypes using high-resolution manometry (HRM). We tested the hypothesis that failure of motor quiescence (FQ) between bisacodyl-induced high amplitude propagating sequences (HAPSs) might predict neuromuscular pathology. METHODS: Eighteen children (10 males, median age: 7.5 years) with refractory STC underwent stationary colonic HRM before segmental colonic resection. Six age-matched constipated children with normal colonic transit served as controls. Colonic resection specimens underwent histopathological analysis. Conventional manometric parameters and area under the curve (AUC) during a 1-min period following bisacodyl-induced HAPSs [PBAUC(1) ], as measure of FQ, were calculated. KEY RESULTS: Numbers of postbisacodyl HAPSs in descending and sigmoid segments were lower in patients than controls (P < 0.01, respectively). Low amplitude propagating sequences (LAPSs) were common prebisacodyl in controls and rare in STC (P < 0.001), whereas postbisacodyl LAPS were more common in STC (P < 0.001). Postbisacodyl, both retrograde propagating contractions and bursts of contractions were present in STC patients only (P < 0.001 and P < 0.01). Postbisacodyl simultaneous pressurization was seen only in STC (P < 0.05 and P < 0.001, in descending and rectosigmoid segments). Histological abnormalities were present in 17/18. Fourteen were neurogenic, one neuro-myogenic, and two myogenic. In segments with HAPS, PBAUC(1) was predictive of colonic neuropathy using a cutoff of 205 mmHg.s(-1) (Sensitivity 100%, specificity 86%, PPV92%, NPV100%). CONCLUSIONS & INFERENCES: PBAUC(1) is increased in multiple colonic segments in neuropathic pediatric STC and constitutes a sensitive and specific biomarker of neuropathy.

Relationship between baseline impedance levels and esophageal mucosal integrity in children with erosive and non-erosive reflux disease.

BACKGROUND: Baseline impedance measurement has been reported to be related to esophageal acid exposure and hypothesized to be a marker of microscopic changes of the esophageal mucosa. Aims of the study were to establish whether any relationship existed between the magnitude of intercellular space diameter (ISD) of esophageal mucosa and baseline impedance levels in children with gastro-esophageal reflux disease (GERD), and to compare baseline impedance levels between children with non erosive (NERD) and erosive (ERD) reflux disease. METHODS: Fifteen children (median age: 11.2 years) with NERD, and 11 with ERD (median age: 9.6 years) were prospectively studied. All patients underwent upper endoscopy. Biopsies were taken 2-3cm above the Z-line, and ISD was measured using transmission electron microscopy. All patients underwent impedance pH-monitoring, and baseline impedance levels were assessed in the most distal impedance channel. KEY RESULTS: Mean (±SD) ISD did not differ between NERD (1.0±0.3µm) and ERD (1.1 ± 0.3 µm, ns). Considering all patients together, no correlation was found between distal baseline impedance and ISD (r: -0.15; ns). Conversely, negative correlations were found between distal baseline impedance and acid exposure time (r: -0.76; P<0.001), long-lasting reflux episodes (r: -0.78; P<0.001), acid reflux episodes (r: -0.62; P<0.001), and acid clearance time (r: -0.79; P<0.001). Distal baseline impedance was significantly lower in ERD [1455 (947-2338) Ω] than in NERD children [3065 (2253-3771) Ω; P<0.01]. CONCLUSIONS & INFERENCES: In children with GERD baseline impedance levels are not useful in predicting reflux-induced ultrastructural changes in the esophageal mucosa, despite their ability to discriminate between NERD and ERD.

Gastric emptying is accelerated following laparoscopic Nissen fundoplication.

AIM OF THE STUDY: The effects on gastric motility following Nissen fundoplication in children are poorly documented. Some paediatric surgeons advocate additional procedures at the same time as fundoplication, such as a pyloroplasty, to enhance gastric emptying. The aim of this study was to determine whether laparoscopic Nissen fundoplication without pyloroplasty affects gastric emptying. METHODS: Gastric emptying was measured before laparoscopic Nissen fundoplication in 8 children after ingestion of a standardised volume of milk for age mixed with 150 mg of (13)C-octanoic acid. None of the patients had a gastrostomy insertion at the time of fundoplication and 2 patients had neurological impairment. Breath samples were collected by breathing into a mask at baseline and every 15 minutes up to 3 hours, and were analysed for (13)CO (2)/ (12)CO (2) ratio by mass spectrometry. Gastric emptying time (t (1/2)) was derived from the curve of (13)CO (2)/ (12)CO (2) ratio against time. The test was repeated in 6 children following Nissen fundoplication at the time of full feeds. Data are reported as mean +/- SD and were analysed by the Mann-Whitney test. RESULTS AND CONCLUSIONS: There were 4 males and 4 females; mean age at surgery was 3.3 +/- 3.0 years. Mean gastric emptying time was 59 +/- 17 min prior to laparoscopic Nissen fundoplication and 45 +/- 4 min following surgery (p = 0.03). Gastric emptying was accelerated in all except one patient. Gastric emptying for liquids is accelerated following Nissen fundoplication in children. Procedures aimed at improving gastric emptying time such as pyloroplasty or pyloromyotomy might not be justified at the time of laparoscopic Nissen fundoplication.

Gastrointestinal complications of epidermolysis bullosa in children.

BACKGROUND: Epidermolysis bullosa (EB) is a group of inherited disorders characterized by skin and mucous membrane fragility. Gastrointestinal (GI) complications have been described in many types of EB and are responsible for significant morbidity. OBJECTIVES: To delineate the nature and frequency of GI complications in a large cohort of paediatric patients with EB and to postulate why some complications occur more commonly in some specific subtypes. METHODS: The case notes of 223 children with EB seen at a national referral centre were examined retrospectively for the presence of GI symptoms, investigations and interventions. RESULTS: GI complications were present in 130/223 (58%) of all patients. In EB simplex, constipation and gastro-oesophageal reflux (GOR) were frequently observed. In junctional EB, failure to thrive and protein-losing enteropathy (PLE) were the prominent GI manifestations. Constipation was common in patients with dystrophic EB (DEB) requiring laxatives and in some cases fibre supplementation. GOR affected three-quarters of those with recessive DEB, two-thirds also having significant oesophageal strictures. Over half of patients with recessive DEB required gastrostomy insertion. Diarrhoea affected a small but significant proportion of children with recessive DEB with macroscopic and/or microscopic changes of colitis in the majority. CONCLUSION: GI problems in EB are very common with subtype specificity for some of these complications. The occurrence of diarrhoea, PLE and colitis in the context of EB has not been highlighted previously, and may arise secondarily to antigenic exposure in the gut lumen as a result of mucosal fragility.

Topical application of mitomycin-C in oesophageal strictures.

BACKGROUND: Benign oesophageal strictures may occur as a complication of caustic ingestion or severe gastro-oesophageal reflux or as a sequela of oesophageal surgery and other fibrosing conditions. The traditional initial treatment of oesophageal strictures is intraluminal dilation; however, even if frequent, this occasionally may not provide adequate oesophageal lumen capacity or give significant symptom-free intervals, and restricturing after dilation is difficult and challenging. Topical postdilation application of an antifibrotic agent, mitomycin-C, in the treatment of an oesophageal stricture has been described. PATIENTS AND METHODS: Eight centres participated, with a total of 16 patients (4 girls), median age 48 (range 0-276) months. The causes of stricture were as follows: caustic (10), post-trachea-oesophageal fistula repair (2), peptic (2), Crohn disease (1), and dystrophic epidermolysis bullosa (1). The median (range) length and diameter of the strictures were as follows: 22 mm (8-50 mm) and 1.5 mm (1-6 mm). Of the 16 patients, 15 had undergone repeated dilations varying from 3 to more than 1000 (daily self-bouginage) before mitomycin-C, and the median interval between dilations was 4 weeks. Mitomycin-C 0.1 mg/mL was applied after dilation for a median time of 3.5 minutes and a median of 3 (1-12) times. RESULTS: Major success, both endoscopic and clinical improvement or cure, occurred in 10 of 16 patients. In 3 of 16 patients the interval period between dilations increased dramatically. Failure of therapy was considered in 3 of 16. All of the patients remained symptom free for a follow-up time of as long as 5 years. CONCLUSIONS: Postdilation application of topical mitomycin-C resulted in major success in 62.5% of patients and partial success in 19%, and it may be a useful strategy in oesophageal strictures of differing causes that are refractory to repeated perendoscopic dilation.

Systemic vasculitis: a cause of indeterminate intestinal inflammation.

OBJECTIVES: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. METHODS: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. RESULTS: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. CONCLUSIONS: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.

Management of fulminating ulcerative colitis in childhood with chimeric anti-CD25 antibody.

Fulminating acute ulcerative colitis (UC) is a potentially life threatening medical emergency. Up to 30% of individuals respond poorly to corticosteroids alone and second line medical or surgical therapies are indicated. We describe the successful use of chimeric anti-CD25 therapy in 4 such children poorly responsive to combined therapy with intravenous steroids and calcineurin inhibitors with a pretreatment predictive risk of colectomy of 85-100%. Clinical disease activity scores normalized within 72 hours of anti-CD25 administration and colonic histology provided evidence of mucosal healing within 10-14 days. None required emergency colectomy. Anti-CD25 is efficacious in fulminating UC and randomized placebo controlled trials appear indicated.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.

Consumerism in healthcare can be detrimental to child health: lessons from children with functional abdominal pain.

AIMS: To determine prognostic indicators in children with severe functional abdominal pain (FAP) and to test the hypothesis that "healthcare consumerism" in these families might be deleterious to the child. METHODS: Retrospective analysis of a cohort of 23 children aged <16 years fulfilling the Rome II diagnostic criteria for FAP during the period December 1997 to February 2001. Poor outcome was defined as continued pain and failure to return to normal functioning >12 months after onset. RESULTS: Poor outcome was associated with refusal to engage with psychological services, involvement of more than three consultants, lodging of a manipulative complaint with hospital management by the child's family, and lack of development of insight into psychosocial influences on symptoms. Three of four adverse prognostic indicators reflected healthcare consumerism by the families. CONCLUSIONS: Actions of families who lack insight into their child's illness may perpetuate FAP in childhood. A culture of parental consumerism in healthcare, however well intentioned, needs to be accompanied by robust systems to protect the interests of the child.

Hypertrophic eosinophilic gastroenteropathy is associated with reduced enterocyte apoptosis.

AIMS: To investigate the cause of grossly elongated villi in four children presenting with obstruction due to a novel form of eosinophilic gastroenteropathy in which there was profound hyperplasia of the intestinal villi with grossly increased villous/crypt ratio and prominent mucosal eosinophilia. Increased eosinophils were also present in the muscularis propria and submucosa. All had intermittent diarrhoea and signs of a protein-losing enteropathy. METHODS AND RESULTS: The cause of the grossly elongated villi was investigated by studying enterocyte proliferation (Ki67), survival factors (bcl-2) and apoptosis (TUNEL) in these patients (n = 4) and normal (jejunum n = 6, ileum n = 6) and disease (n = 6) controls. The most remarkable finding was that apoptotic enterocytes were undetectable in the elongated villi. CONCLUSIONS: It seems likely that a defect in the regulation of apoptosis of the epithelium occurs which could explain the remarkable hyperplasia of the villi seen.

Eosinophilic myenteric ganglionitis is associated with functional intestinal obstruction.

The diagnostic features and clinical course of three children (aged 1 month to 15 years) with severe functional intestinal obstruction and inflammation of the colonic lamina propria and myenteric plexus are described. The myenteric inflammatory infiltrate was eosinophil predominant with none of the immunological characteristics of lymphocytic ganglionitis. Neurones in the myenteric ganglia expressed the potent eosinophil chemoattractant interleukin 5. None responded to dietary exclusion but all three responded symptomatically to immunosuppression/anti-inflammatory treatments. Eosinophilic ganglionitis is associated with a pseudo-obstructive syndrome which is amenable to anti-inflammatory treatment.

Faecal elastase 1 concentration is a marker of duodenal enteropathy.

BACKGROUND: Measurement of faecal elastase (FE1) is used widely to screen for pancreatic exocrine insufficiency (PI). FE1 does not allow differentiation of primary from secondary PI. AIMS: To investigate the relation between duodenal morphology and FE1 in children with secondary PI resulting from primary gastrointestinal diseases. METHODS: A group of 51 children underwent small intestinal biopsy and FE1 measurement. Villus to crypt ratio (VCR) and inflammation within the lamina propria of duodenal mucosal biopsy specimens were scored and compared with FE1 values. RESULTS: In 51 children from nine diagnostic categories, a highly significant correlation between FE1 and both duodenal morphology and inflammation was found. CONCLUSION: Small bowel enteropathy is associated with low FE1 concentrations, indicative of secondary exocrine pancreatic insufficiency.

Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.

We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy.

p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.

Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.